Implantable cardioverted defibrillators: 40 years of history and beyond

KEYWORDS:

• ICD
• defibrillator
• SCD
• sudden cardiac death
• trials

1. Introduction

More than forty years ago, physicians started to implant cardioverter defibrillators (ICDs), first in patients survived after a cardiac arrest [1]. This disruptive technology has now become the standard of care for primary and secondary prevention of sudden death in patients with heart disease [2].

Sudden cardiac death (SCD) is a phenomenon not completely understood; its numbers are stable, even though lots of interventions are put in place to reduce its incidence: from pharmacological therapy to behavioral advice, to prompt emergency care access in different countries outside the hospital [3]. Coronary heart disease continues to be the most known and advocated cause of sudden cardiac death; nevertheless, a relevant proportion of cases of SCD occurs in patients without prior history of severe heart condition [3].

A relevant growth in ICD implants is expected in the world for the upcoming years, considering the high rate of implantation in high-income countries and substantial variability among utilization in different settings [4].

There are many different conditions that can result in ICD indication; however, the main reason for implant can be summarized as primary and secondary prevention, with the former responsible for majority of implants (from 60 to 79% of cases) [5,6].

During the last two decades, a relevant number of clinical trials (see Table 1) demonstrated the benefit of ICD therapy in secondary prevention and in primary prevention, too. The two main subgroups of patients investigated for primary prevention, on the basis of reduced Left Ventricular Ejection Fraction (LVEF), were historically divided into ischemic and nonischemic heart diseases [7–9].

Table 1. Pivotal clinical trials in ICD therapy.

Year	Study	Patients	Indication	Study population	Conclusions
1996	MADIT	196	Primary	Ischemic; LVEF: ≤35%; NYHA: I–III; asymptomatic NSVT or inducible VT on EPS	54% relative risk reduction in mortality with ICD
1997	AVID	1013	Secondary	Symptomatic VT; survivors of SCD; LVEF: ≤40%	31% relative risk reduction in mortality with ICD
1999	MUSTT	704	Primary	Ischemic; LVEF: <40%; asymptomatic NSVT	51% relative risk reduction in mortality with ICD
2000	CASH	288	Secondary	SCD survivors, unstable VT	23% relative risk reduction in mortality with ICD
2002	MADIT-II	1232	Primary	Ischemic: LVEF: <30%; more than 30 days from the onset of myocardial infarction	31% relative risk reduction in mortality with ICD
2004	DEFINITE	458	Primary	Nonischemic (DCM); LVEF ≤35% NSVT or premature ventricular complexes (≥10 beats/hour) on Holter	ICD reduced rate of death from any cause (7.9% versus 14%)
2004	DINAMIT	674	Primary	Ischemic, recent MI within 4–40 days; LVEF: ≤35%; impaired HR variability	No reduction in all-cause death with ICD therapy but reduction in arrhythmic deaths
2004	COMPANION	1520	Primary	Ischemic and nonischemic; NYHA: III–IV; LVEF QRS: >120 msec	Approximately 20% reduction in composite of all-cause hospitalization or death with CRT
2005	SCD-HeFT	2521	Primary	Ischemic and nonischemic; LVEF <35%; NYHA: II–III	23% relative risk reduction in mortality with ICD
2016	DANISH	1116	Primary	Nonischemic; LVEF: ≤35; NYHA: II–III (IV if for CRT); optimal medical therapy, including CRT	No mortality reduction with ICD; 3% absolute reduction in SCD mitigated by 1.5% absolute risk of device related infection

CM: cardiomyopathy; CRT: cardiac resynchronization therapy; DCM: dilated cardiomyopathy; EPS: electrophysiology study; HR: heart rate; ICD: implantable cardioverter defibrillator; LVEF: left ventricular ejection fraction; NSVT: nonsustained ventricular tachycardia; NYHA: New York Heart Association; SCD: sudden cardiac death; VT: ventricular tachycardia.

2. Different etiologies, beyond LVEF

Even if different attempts were made to investigate possible predictors of SCD in large populations, LVEF is the only parameter strongly recommended by guidelines and used in clinical practice, in order to make the decision about ICD implantation for primary prevention in patients with heart failure (HF). However, this parameter seems to be not perfect in assessing the population at risk. In this context, the benefit of ICDs on all-cause mortality has been questioned after the results of the DANISH trial [10].

Some other clinical predictors of ventricular arrhythmias were investigated in the last few years, but there is still lack of consensus about their use in clinical practice. These important added predictors could be game changer, especially in situations where there is limited access to healthcare and technology or when the implantation of a defibrillator has a huge impact on quality of life and social reflections [11]. Late gadolinium enhancement assessed by cardiac magnetic resonance (CMR) has emerged as a good, yet not perfect, predictor of SCD and appropriate ICD shocks in dilated cardiomyopathy. In the next future, a better understanding of its quantification and stratification could be of further help in depicting a crucial role of imaging in guiding intervention in heart failure.

It is particularly true that, for some relatively rare, selected population, the use of multiparametric scores instead of a single variable was found to better predict arrhythmic mortality and is now the cornerstone to guide ICD implant. The HCM risk-SCD [12] is demonstrated to effectively predict sudden death in patients with Hypertrophic Cardiomyopathy (HCM) and is nowadays implemented in guidelines to treat this disease [13]. Some other scores are still on their way to gain relevance in other settings, such as in Arrhythmogenic Right Ventricular Cardiomyopathy [14] or nonischemic dilated cardiomyopathy [15,16].

3. Current gaps

Even after the enormous advances made by the synergic interplay between physicians and industries in the prevention of sudden death, there may still be some unaddressed questions. The scientific community in the next future expressed the need for research in several fields:

• indications for ICD in patients with heart failure with mid-range and preserved LVEF [16]

• optimal selection of ICD candidates among those with reduced LVEF [16]

• the role of the ICD in patient subgroups such as elderly, chronic kidney failure or multiple comorbidities [17]

• novel biomarkers and risk stratification of patients who are now candidates to ICD implant and how to use them to select new subgroups at risk of SCD [17]

• build strong evidences about benefit from primary prevention ICD in patients with arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, and inherited cardiac channelopathies [17]

• interdisciplinary approaches to guide ICD implant including cardiologists, geneticists, epidemiologists, and basic and translational scientists especially in patients with preserved LVEF [18]

• better definition of indication and application of wearable defibrillators and subcutaneous ICD [17,18].

4. Recent and ongoing trials

Despite the huge amount of research and progress regarding cardiac defibrillators in the recent past, a large number of studies are about to be completed or still ongoing. They focus on expanding and restricting ICD indication, especially in patients with nonischemic etiology of heart disease and heart failure with preserved ejection fraction. Both randomized and nonrandomized prospective studies have been registered in dedicated websites. They will answer different questions that are still open regarding the impact of ICD in rare diseases or the use of different imaging techniques to guide risk stratification together with invasive tests [19]; these research studies may be in the future game changers for cardiologists and especially for cardiac electrophysiologists taking care of patients who are now excluded from ICD implant. Another important field of research is about the application and perfection of new technologies such as subcutaneous ICD and its implant technique; in the last few years, some different reports highlighted strength and pitfalls of this technology, the first redesigning the concept of implantable defibrillator after three decades [20,21]. Novel designs for defibrillation leads and new devices implanted outside the vascular system are also about to appear in clinical experimentations and ultimately in clinical practice (see Table 2).

Table 2. ongoing studies in the field of ICD therapy.

Study short name	No. and year of registration	Indication	Patients’ enrolment	Study title	Question addressed
PROTECT-ICD	NCT03588286, 2018	Primary	1058	Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction	Can an EPS help decide to implant or not ICD in patients after MI with LVEF <40%?
EV ICD CA	NCT05049720, 2021	Class I or IIa according to guidelines	200	ExtraVascular Implantable Cardiac Defibrillator Continued Access Study	Describe a population with extravascular ICD.
CMR GUIDE DCM	NCT03993730, 2019	Primary	1880	Cardiovascular Magnetic Resonance GUIDEd Insertion of Implantable Cardiac Defibrillator in Dilated CardioMyopathy	Is an ICD superior to loop recorder in patients with DCM and LVEF <45%?
	NCT04505007, 2020	Primary	200	Guideline-Directed Medical Therapy in Patients After Implantation of Implantable Cardioverter Defibrillators to Improve Long-Term Outcomes	Do patients with heart failure and ICD need a structured team to implement guideline-directed medical therapy?
DanICD	NCT04576130, 2020	Secondary	1200	A Danish ICD study in Patients With Coronary Artery Disease Resuscitated From Ventricular Fibrillation	Is ICD indicated in secondary prevention after complete revascularization and with LVEF >35%?
ASE	NCT03802110, 2019	Primary and secondary	42	Acute Feasibility Investigation of a New S-ICD Electrode	Describe characteristic of a new s-ICD electrode configuration
PRAETORIAN-DFT	NCT03495297, 2018	Indication according to guidelines	965	A Randomized Trial of S-ICD Implantation With and Without Defibrillation Testing	Can the defibrillation test be omitted after S-ICD implant when the position is confirmed with PRAETORIAN score?
CHAGASICS	NCT01722942, 2012	Primary	1100	Amiodarone Against ICD Therapy in Chagas Cardiomyopathy for Primary Prevention of Death	Is ICD better than amiodarone in Chagas cardiomyopathy patients with documented nonsustained ventricular tachycardia in preventing SCD?
ReCONSIDER	NCT04246450, 2020	Primary	675	Arrhythmic Risk Stratification in Nonischemic Dilated Cardiomyopathy	Can we find a new way to stratify arrhythmic risk in patients with nonischemic dilated cardiomyopathy combining noninvasive risk factors and electrophysiologic studies?
CMR_GUIDE	NCT01918215, 2013	Primary	1055	Cardiac Magnetic Resonance GUIDEd Management of Mild-moderate Left Ventricular Systolic Dysfunction	Is an ICD superior to loop recorder in patients with HF and LVEF >35 and <50% measured by CMR?
LEADR	NCT04863664, 2021	According to guidelines	500	Lead EvaluAtion for Defibrillation and Reliability	To describe new-generation ICD lead in a wide population
	NCT03530904, 2018	According to guidelines	400	Comparison Between Early and Late Mobilization After Cardiac Device Implantation	Are 4 hours enough or is better a bed restriction till the morning after the procedure of CIED implant?

CIED: implantable cardiac devices; CMR: cardiac magnetic resonance; DCM: dilated cardiomyopathy; ICD: implantable cardioverter defibrillator; LVEF: left ventricular ejection fraction; SCD: sudden cardiac death; s-ICD: subcutaneous ICD.

5. Conclusions

In the last forty years, implantable cardioverter defibrillators have been established as the most effective method for preventing sudden cardiac death, and none other interventions proved better to do so. There are still issues to be addressed by constant evolution and dedicated research, and the next decade will surely bring improvements to this technology. Physicians and health care managers should keep on constantly pursuing the optimal application of implantable defibrillators among cardiac patients.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.